Niemann-Pick disease, type C1: genes and variants

Genes linked to Niemann-Pick disease, type C1

• NPC1: NPC intracellular cholesterol transporter 1

  It moves cholesterol and other lipids out of late endosomes and lysosomes so they can be redistributed throughout the cell. Biallelic loss-of-function variants cause Niemann-Pick disease type C with progressive neurologic and visceral lipid-storage disease.

  175 disease-causing and 469 uncertain variants in NPC1 are linked to Niemann-Pick disease, type C1.

Weakly linked (only a few uncertain records): SMPD1.

Where Niemann-Pick disease, type C1 variants cluster

• NPC1 Lumenal (positions 854–1097): 54 of 175 disease-causing changes, 1.6× more than its size predicts.
• NPC1 Transmembrane (positions 1151–1171): 9 of 175 disease-causing changes, 3.1× more than its size predicts.
• NPC1 Transmembrane (positions 1195–1215): 8 of 175 disease-causing changes, 2.8× more than its size predicts.
• NPC1 Transmembrane (positions 1125–1145): 6 of 175 disease-causing changes, 2.1× more than its size predicts.
• NPC1 Cytoplasmic (positions 1172–1194): 6 of 175 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Niemann-Pick disease, type C1

Showing 60 of 175.

Uncertain variants in Niemann-Pick disease, type C1 that look disease-causing

Which prediction tools work for Niemann-Pick disease, type C1

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 92 out of 100
• phyloP: 82 out of 100

Diseases related to Niemann-Pick disease, type C1

• Niemann-Pick disease, type A, also linked to NPC1
• Niemann-Pick disease, type C, also linked to NPC1
• Sphingomyelin/cholesterol lipidosis, also linked to NPC1
• Dystonic disorder, also linked to NPC1

Frequently asked questions

Which genes are linked to Niemann-Pick disease, type C1?

In CATVariant, Niemann-Pick disease, type C1 is linked to 1 analyzed protein: NPC1 (NPC intracellular cholesterol transporter 1).

How many genetic variants are linked to Niemann-Pick disease, type C1?

700 variants: 175 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 469 are of uncertain significance or have conflicting reports.

Which uncertain variants in Niemann-Pick disease, type C1 look disease-causing?

13 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NPC1 C479Y, NPC1 R389C, NPC1 N1156T, NPC1 H512R and NPC1 G1012C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Niemann-Pick disease, type C1?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 117 disease-causing and 30 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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